Immunosuppression is associated with many diseases caused by organisms that are normally non-pathogenic. Oropharyngeal candidiasis (OPC), caused by the yeast Candida albicans, is a major opportunistic infection associated with chemotherapy, AIDS, transplant drugs, xerostomia, Sjogren's Syndrome and congenital immunodeficiency. C. albicans also causes vaginal yeast infections as well as a form of disseminated candidiasis, the latter of which is the 4th most common cause of hospital- acquired infections. Interestingly, AIDS patients are not more susceptible to vaginal or disseminated candidiasis than the normal population, indicating that CD4+ T cells play a more important role in protecting the oral mucosa against candidiasis compared to other anatomical sites. Th17 cells represent a distinct lineage of CD4+ T lymphocytes, whose discovery in 2005 revolutionized our understanding of immunity to extracellular microbes and autoimmunity. Th17 cells are also a major sentinel cell found in abundance at mucosal surfaces, including the lung, gut and oral cavity. Our laboratory recently demonstrated that Th17 cells comprise the major T cell subset responsible for effective host immunity against OPC. The focus of this grant application is to determine in detail exactly how the Th17 pathway and related cytokines mediate immunity to OPC, using both mouse and human models. Specifically, we will evaluate the role of the Th17 axis of immunity in (1) promoting STAT3-dependent resistance to OPC, (2) driving expression of anti-microbial peptides in the oral mucosa, (3) controlling salivary gland function and candidacidal killing activity, and (4) regulating Th17 cell dynamics during OPC in vivo. Collectively, these experiments will help to elucidate the fundamental immune mechanisms used by Th17 cells to prevent C. albicans from becoming pathogenic. Defining critical immune pathways may lead to rational avenues of therapeutic intervention for OPC (e.g., cytokine or anti-cytokine drugs, anti-microbial peptides). Understanding how Candida-specific T cells are generated and activated may also lead to more effective vaccines, which is sorely needed in at-risk populations. Conversely, anti-cytokine drugs that target Th17 cells in autoimmunity are in clinical trials, and this work may reveal potential side effects of these drugs such as OPC.